Autosomal-Recessive Hypophosphatemic Rickets Is Associated with an Inactivation Mutation in the ENPP1 Gene

Human disorders of phosphate (Pi) handling and hypophosphatemic rickets have been shown to result from mutations in PHEX, FGF23, and DMP1, presenting as X-linked recessive, autosomal-dominant, and autosomal-recessive patterns, respectively. We present the identification of an inactivating mutation i...

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Bibliographic Details
Published in:American journal of human genetics 2010-02, Vol.86 (2), p.273-278
Main Authors: Levy-Litan, Varda, Hershkovitz, Eli, Avizov, Luba, Leventhal, Neta, Bercovich, Dani, Chalifa-Caspi, Vered, Manor, Esther, Buriakovsky, Sophia, Hadad, Yair, Goding, James, Parvari, Ruti
Format: Article
Language:English
Subjects:
Adolescent
Adult
Amino Acid Sequence
Base Sequence
Biological and medical sciences
Calcium
Conserved Sequence
Familial Hypophosphatemic Rickets - enzymology
Familial Hypophosphatemic Rickets - genetics
Fundamental and applied biological sciences. Psychology
Gene Silencing
General aspects. Genetic counseling
Genes
Genes, Recessive - genetics
Genetic Diseases, X-Linked
Genetic Predisposition to Disease
Genetics
Genetics of eukaryotes. Biological and molecular evolution
Humans
Medical disorders
Medical genetics
Medical sciences
Molecular and cellular biology
Molecular Sequence Data
Mutation
Mutation - genetics
Nephrology. Urinary tract diseases
Nephropathies. Renovascular diseases. Renal failure
Phosphates
Phosphoric Diester Hydrolases - chemistry
Phosphoric Diester Hydrolases - genetics
Polymorphism, Single Nucleotide - genetics
Pyrophosphatases - chemistry
Pyrophosphatases - genetics
Tubulopathies
Young Adult
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Summary:Human disorders of phosphate (Pi) handling and hypophosphatemic rickets have been shown to result from mutations in PHEX, FGF23, and DMP1, presenting as X-linked recessive, autosomal-dominant, and autosomal-recessive patterns, respectively. We present the identification of an inactivating mutation in the ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene causing autosomal-recessive hypophosphatemic rickets (ARHR) with phosphaturia by positional cloning. ENPP1 generates inorganic pyrophosphate (PPi), an essential physiologic inhibitor of calcification, and previously described inactivating mutations in this gene were shown to cause aberrant ectopic calcification disorders, whereas no aberrant calcifications were present in our patients. Our surprising result suggests a different pathway involved in the generation of ARHR and possible additional functions for ENPP1.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2010.01.010